PROJECT SUMMARY. Trisomy 21 (T21) causes a different disease spectrum in people with Down syndrome (DS), protecting these individuals from some diseases, while strongly predisposing them to others. For example, >50% of adults with T21 are affected by one or more autoimmune conditions, including a wide range of immune skin conditions. Unfortunately, the mechanisms driving this different disease spectrum are poorly understood, which creates a challenge in the clinical management of DS. We recently discovered that T21 causes consistent activation of the interferon (IFN) response across diverse cell types, which is likely due to the fact that four of the six IFN receptors are encoded on chr21. Accordingly, T21 cells are hypersensitive to IFN stimulation, display hyperactivation of JAK/STAT signaling, and overexpress IFN-Stimulated Genes. Furthermore, dozens of inflammatory cytokines are dysregulated in people with DS, and T21 drives production of potent neurotoxic metabolites via the IFN- inducible kynurenine pathway. Therefore, we hypothesize that hyperactivation of IFN signaling drives immune dysregulation and various pathologies in DS, and that pharmacological inhibition of IFN signaling could have multidimensional therapeutic benefits in this population. Accordingly, we propose here to complete a first-in-kind clinical trial for a JAK inhibitor in DS. our Specific Aims are: 1. To define the safety profile of JAK inhibition in people with Down syndrome. We will perform an open- label Phase II clinical trial for Tofacitinib, a JAK1/3 inhibitor, in people with DS and an active immune skin condition, with the main primary endpoint being the assessment of safety. 2. To determine the impact of JAK inhibition on the immune dysregulation caused by trisomy 21. Using blood samples collected during the trial, we will define the impact of JAK inhibition on a) IFN scores derived from the transcriptome of white blood cells, b) circulating levels of inflammatory cytokines elevated in people with DS, c) levels of neurotoxic metabolites in the IFN-inducible kynurenine pathway, and d) levels of key autoantibodies involved in autoimmune thyroid disease and celiac disease, two common co-occurring conditions in DS. 3. To define the impact of JAK inhibition on immune skin conditions in Down syndrome. Using proven metrics currently employed in clinical trials of JAK inhibitors for immune skin conditions, our main secondary endpoint will be to determine whether JAK inhibition reduces skin pathology in DS. 4. To characterize the impact of JAK inhibition on cognition and quality of life in Down syndrome. Using a battery of tests to evaluate cognition in DS, we will explore the impact of JAK inhibition on diverse cognitive functions. Decreased skin pathology may also affect overall perceived health and enjoyment, as well as have social implications, which will be measured by quality of life assessments.